Wednesday, March 12, 2014

Magic Methyl Effect

Character picture
taken from “Wreck It Ralph”

This week, the
newest paper in our sulfinate chemistry series was published online,
featuring a radical-based C–H methylation of heterocycles. Indeed, as we
embarked on “mission methylation,” we were mesmerized by the “magic methyl
effect” where appending a single methyl group in the appropriate place could
improve the biological activities of pharmaceuticals as much as 100-fold. (See
the elegant review by Tim Cernak: Angew.Chem. Int. Ed. 2013, 52, 12256; there are also two
interesting blog entries “In the Pipeline” about the Magic Methyl Group in 2011
and 2013.

However, our interest in arene and
heteroarene methylation dated way before the aforementioned disclosures, even
before our first report of sulfinate chemistry. Our initial inspiration came
from the classic Fenton chemistry (some 30 years ago), and our lab initially
set out to generate methyl radicals from DMSO under oxidative conditions.
Various other radical surrogates were surveyed, including the methylsulfinate
salt. However, none of these endeavors were successful. Reactions proceeded
with very low conversions, and reaction monitoring/product isolation was
incredibly challenging since the product and starting material almost had
identical polarity.

We then realized that an indirect
methylation reagent would be perhaps more useful—we would incorporate
substitutions to our radical precursor which could fine-tune radical reactivity
and ease product purification. Thus, we synthesized the TMS sulfinate salt. To
our dismay, this reagent exhibits poor reactivity, forcing us to consider other
heteroatoms, including boron and phosphorus—however, sulfinate salts containing
these elements were difficult to access and didn’t show satisfactory
reactivity. Sulfur did us the magic! We successfully made the bench-stable
(phenylthio)methanesulfinate (PTMS) and were elated to discover that the •CH2SPh
radical adds to pyridines. Nevertheless, the thioether moiety was highly labile
under reaction conditions, undermining the robustness of the reagent. However,
upon changing the thioether to the corresponding sulfone, we finally identified
a more robust and reactive reagent. PSMS is not only robust, but the sulfone
group also allows for easy separation of product from starting material as
illustrated by the TLC plate below. While one can hardly differentiate N-Boc-tryptophan methyl ester (1) and its methylated analogue (3), the (phenylsulfonyl)methylated product
(2) stood out distinctively.

Admittedly, the preparation of the salt
(PSMS) wasn’t anything trivial in the beginning: originally, we developed a
four-step sequence (shown below) using benzothiazole as a leaving group during
the reductive cleavage. We could only obtain ca. 8 g of PSMS over a period of
one week; furthermore, the sequence included two chromatographical separations,
which can be really tedious on large scales. But then the good news came: when
we became concerned over the utility of the salt, Aaron from Pfizer came to the
rescue as he suggested a one-step preparation of PSMS using DABSO (Org. Lett.2014, 16, 150). Eddie (Chung-Mao)
skillfully executed this idea and now we have a column-free procedure. This new
procedure, which is described in the paper, could provide 25 grams of PSMS in
two days (one chemist in a single batch); PSMS prepared in this manner is
completely free from ZnBr2.

If anyone has questions about this methylation project, I'd be very
happy to answer them!

Thanks! The first step was following a known procedure (Synthesis, 1980 , 952 - 953). For the second step, alkylation of PhSH, we didn’t conduct a systematic base screen and Cs2CO3 in CH3CN at rt worked very well. Other bases (such as NaH in THF) might also work but we didn’t tried that. High temperature should be avoided since we observed the formation of 2-(phenylthio)benzothiazole during this alkylation (in small amount). This route has not been published yet.